Use of injectable biomaterials for the repair and augmentation of the anal sphincters

ABSTRACT

This invention discloses methods of repairing structurally defective or inadequately functioning muscles of the anal sphincter and methods of improving the competency of incompetent anal sphincters by administering an effective amount of an injectable biomaterial into the defect or into the anal sinuses. Preferred biomaterials to be used in this invention are collagen formulations.

TECHNICAL FIELD

This invention is in the field of medical implants and prostheses. Moreparticularly, it concerns a nonsurgical technique for repairingstructurally defective or inadequately functioning anal sphincters andfor improving the competency of anal sphincters by injectingbiomaterials into the defect or into the anal sinuses.

BACKGROUND OF THE INVENTION

Anal sphincters are muscular structures that assist in controlling theflow of body wastes (feces and flatus) from the colon. The internal analsphincter (IAS) and the external anal sphincter (EAS) encircle the analcanal and comprise the anorectal ring. The IAS is a thickening of thegastrointestinal smooth muscle; it maintains continence at rest. The EASis composed of striated, voluntary muscle. The EAS, the puborectalis,and the levator ani muscles work in concert to prevent leakage of flatusand feces when there is an increase in abdominal pressure or when theinternal anal sphincter relaxes after rectal distention.

When one or both sphincters become defective or incompetent, the controlof feces and/or flatus is impaired. Incontinence of the feces and flatusis socially and psychologically disabling for the afflicted patient. Itis a major factor prejudicing the rehabilitation and placement prospectsof the elderly and disabled, preventing many of them from being caredfor at home.

The normal mechanisms of anorectal continence include the motor functionof the anal sphincters and pelvic floor muscles, the role of the rectumand sigmoid colon as a fecal reservoir with capacitance and complianceand as a propulsive force with intrinsic motor activity, the effects ofstool consistency, volume and delivery rate, the anorectal angle, andanorectal sensation. It is the coordinated integration of these factorsthat confers continence.

There are two distinct etiologies for anorectal incontinence. The mostcommon cause of anorectal incontinence is a structural deformity due toanatomic disruption of the sphincter mechanism, which may be caused byobstetric injuries (perineal laceration and improperly performed medianepisiotomies), complications of fistula or fissure surgery (keyholedeformities), traumatic injuries (e.g., impalement injuries), or cancer.Alternatively, anorectal incontinence may result from deterioration ofthe sphincter muscles due to age, congenital disorders, systemic andmetabolic diseases, acquired neurological defects, and diseases of thecolon and rectum.

Present treatment modalities for anorectal incontinence includenonsurgical and surgical therapy. Nonsurgical therapy for incontinencemust be tailored to each individual: patients suffering from urgencyincontinence may benefit from the use of bulk-forming agents andlaxatives or enemas; individuals with minor degrees of incontinence mayfind biofeedback and perineal strengthening exercises beneficial inalleviating symptoms of seepage and occasional loss of control.

Current nonsurgical treatments for anorectal incontinence include theuse of electrical stimulation to improve contraction of the sphinctermuscles and the use of anorectal plugs which are designed to expandpost-insertion.

U.S. Pat. Nos. 3,650,275 and 3,749,100 describe an electrostimulationdevice to maintain contraction of the sphincter muscle. A magneticartificial anus closing device is described in U.S. Pat. No. 3,952,726.U.S. Pat. No. 4,209,009 discloses an anus closure tampon withnonhomogeneous sections having differential diametrical compressibilityto provide a plug effect. U.S. Pat. No. 4,401,107 describes anintestinal control valve arranged to surround the anal-terminatingdescending intestine, thereby functioning as an artificial sphincter. Adevice comprising three inflatable chambers (the first, positionedoutside the rectum; the second, within the anal sphincter muscle; thethird, outside the body between the buttocks) to maintain analcontinence is disclosed in U.S. Pat. No. 4,686,985. U.S. Pat. Nos.4,781,176 and 4,969,902 teach an artificial anus comprising a hollowtubular support member and a releasable plug for sealing closed thesupport member. A pressure transducer or electrical contact is providedon the support member and connected to an electrode in contact with thepatient's skin, so that when the colon becomes pressurized the patientis signalled that the plug should be released. U.S. Pat. No. 4,904,256describes a magnetic artificial anus assembly, having a sphincterfunction similar to the natural anus, which comprises an annular bagstructure filled with a magnetic fluid and a plug structure having amagnet member.

Surgical therapy must also be individualized, and is directed either at(i) repair of the disrupted sphincter or (ii) augmentation (withautogenic transplanted muscle or commercially available Silastic sheetprostheses) of existing structures to improve physiologic function.Diverting colostomy is rarely necessary.

Unfortunately, there are inherent difficulties and risks in thesecorrective methods. For example, anorectal plugs will often causeinfection, fibrosis of the mucosa, or muscularis of the bowel near theplug. Also, patients complain about the discomfort and inconvenience oftemporary plugs that function similar to absorbent pads. An artificialsphincter may extrude or malfunction, necessitating additional surgeryor corrective action. Surgery also can result in infection or othercomplications, such as host-graft rejection, and is a significantexpense. Therefore, it is desirable to treat anal sphincter deficiencieson a cost-effective, outpatient basis, such that the inherentdifficulties presented by the current methods are avoided.

Injectable biomaterials, e.g., Polytef® paste (polytetrafluoride,Mentor), injectable liquid silicone, and collagen, have been used toaugment incompetent lower esophageal sphincters and urinary sphinctersover the past ten years. These so-called sphincters, however, are nottrue sphincteric muscles because they are controlled by pressurechanges, rather than neurological stimulation from the brain.Furthermore, the use of injectable biomaterials for treating loweresophageal and urinary sphincters is simply to bulk up the surroundingtissue by injecting the biomaterial to close the respective orifice.

SUMMARY OF THE INVENTION

In contrast to the lower esophageal and urinary sphincters, the analsphincters are highly vascular and muscular areas with involuntarycontracture by the IAS and voluntary contracture by the EAS mechanisms.If either of these sphincters is rendered incompetent due to any of thepreviously described causes, varying degrees of anorectal incontinencemay be the result. One aspect of this invention is a method forrepairing or replacing structurally defective or inadequatelyfunctioning muscles of the anal sphincters by administering an effectiveamount of an injectable biomaterial perianally into the defect orstructural deformity. The invention further includes a method forimproving the competency of incompetent anal sphincters by administeringan effective amount of an injectable biomaterial into the anal sinusesbetween the blood vessels. Another aspect of the invention is a methodof inducing wound healing of a structurally defective anal sphincter byadministering an effective amount of an injectable biomaterialcontaining one or more wound healing agents, such as a biologicallyactive protein growth factor, into the defect. In some instances, thebiomaterial, particularly when it is a collagen material, may create afibrolytic bridge between the ends of the sphincter.

A method for repairing defective or incompetent anal sphincter musclesideally would include a nonsurgical procedure utilizing biocompatiblematerials that are non-immunogenic, have a low risk for infection, andare easy to administer. The present invention provides such an effectivemethod for repairing defective or incompetent anal sphincter muscles byadministering an injectable biocompatible biomaterial.

DETAILED DESCRIPTION OF THE INVENTION

The invention is a method for repairing structurally defective orinadequately functioning muscles of the anal sphincters by perianallyadministering an effective amount of an injectable biomaterial(s), withand without wound healing agents, into the defect or structuraldeformity. The invention further comprises a method for improving thecompetency of incompetent anal sphincters by administering injectablebiomaterials into the anal sinuses between the blood vessels.Improvement of the sphincter's competence will improve fecal and flatuscontinence and increase the anorectal squeeze pressure, resulting inimproved control.

The term "incompetent," as used herein, refers to sphincter muscles thatare inadequately functioning or nonfunctioning due to the deteriorationof the sphincter muscles or due to a structural deformity caused byanatomic disruption of the sphincter mechanism.

The term "improving the competency," as used herein, means augmentingthe existing sphincter muscle to improve the patient's baselinecontinence level. Improved competence would result in increased restingsqueeze pressure, maximal squeeze pressure, and threshold volume as canbe measured by standard manometric tests. An alternative method formeasuring improved competence is by a change in clinical grading frommajor incontinence to minor incontinence to continence. Majorincontinence occurs when there is deficient control or lack of controlof stool of normal consistency. Minor incontinence is a disorder inwhich there is partial soiling or occasional incontinence of flatus orof loose or watery stools. Continence is when there is no soiling oroccasional incontinence due to flatus or loose or watery stools.

The term "effective amount" as used herein, means the quantity ofbiomaterial needed to repair anal sphincter muscle or to achieveimproved competence as measured by standard manometry or the quantity ofwound healing agents needed to achieve improved healing. The effectiveamount of biomaterial administered may vary depending on the patient'sown ability to absorb or break down the biomaterial, the consistency andconcentration of the material, and the site and condition being treated.Furthermore, the biomaterial may be administered over a number oftreatment sessions to achieve and maintain improved competence asmeasured by standard manometry.

The biomaterial used in the invention may be selected from a number ofsources; however, it must be injectable, biocompatible, essentiallynon-immunogenic, and persist at the site of placement for at least threemonths. Alternatively, the biomaterial may be an aqueous suspension of abiopolymer with a biocompatible fluid lubricant to improve the intrusionof the biopolymer into the tissue. See U.S. Pat. No. 4,803,075, which isincorporated herein by reference. Commercially available suspensions ofa biopolymer and fluid lubricant may be obtained from Bioplasty, Inc.(Minneapolis, Minn.) under the tradename Bioplastique Micro-Implants.Fluid lubricants may include: hyaluronic acid, dextran sulfate, dextran,succinylated non-crosslinked collagen, methylated non-crosslinkedcollagen, glycogen, glycerol, dextrose, maltose, triglycerides of fattyacids, egg yolk phospholipids, heparin, and the like. Biopolymers mayinclude: atelopeptide fibrillar, crosslinked or non-crosslinkedcollagen, gelatin beads, polytetrafluoroethylene beads, silicone rubberbeads, hydrogel beads, silicon carbide beads, glass beads, and the like.

A preferred biomaterial comprises a collagen formulation. Most preferredare those collagen formulations wherein the collagen is atelopeptidefibrillar, crosslinked, or non-crosslinked collagen, or collagen mixedwith a mineral material. Collagen is a major protein component of bone,cartilage, skin, and connective tissue in animals. Collagen in itsnative form is typically a rigid, rod-shaped molecule approximately 300nanometers (nm) long and 1.5 nm in diameter. It is composed of threecollagen polypeptides which form a tight triple helix. The collagenpolypeptides are characterized by a long midsection having the repeatingsequence --Gly--X--Y--, where X and Y are often proline orhydroxyproline, bounded at each end by the "telopeptide" regions, whichconstitute less than about 5 percent (%) of the molecule. Thetelopeptide region of the collagen chains are typically responsible forthe crosslinking between chains and for the immunogenicity of theprotein. Collagen occurs in types, of varying physical properties; themost abundant are Types I-III.

The collagen used in the invention may be collected from any number ofmammalian sources, such as bovine or porcine corium and human placenta.The preparation of purified, substantially nonantigenic collagen insolution from the skin is basically a three-step process involvingsolubilization, enzyme treatment, and purification. See U.S. Pat. Nos.4,140,537 and 4,488,911; which are incorporated herein by reference. Theterm "collagen" or "collagen material" as used herein refers to allforms of collagen, including those which have been processed orotherwise modified.

Preferred collagens are treated to remove the immunogenic telopeptideregions ("atelopeptide collagen"), are soluble, and will have beenreconstituted into the fibrillar form ("atelopeptide fibrillar"). Thereconstituted fibrillar collagen may optionally be crosslinked usingmethods generally known in the art, such as by heat, radiation, orchemical crosslinking agents. Commercially reconstituted collagens areavailable under the tradenames Zyderm Collagen Implant and ZyplastCollagen Implant (Collagen Corporation, Palo Alto, Calif.). See U.S.Pat. Nos. 4,582,640 and 3,949,073; which are incorporated herein byreference.

U.S. Pat. No. 4,424,208; incorporated herein by reference, discloses animproved collagen formulation suitable for use in soft tissueaugmentation. The formulation comprises reconstituted fibrillaratelopeptide collagen in combination with particulate, crosslinkedatelopeptide collagen dispersed in an aqueous medium. The addition ofparticulate crosslinked collagen improves the biomaterial's persistence,or ability to resist shrinkage following injection.

U.S. Pat. No. 4,557,764; incorporated herein by reference, discloses a"second nucleation" collagen precipitate which exhibits a desirablemalleability and putty-like consistency. Collagen is provided insolution [e.g., at 2-4 milligrams per milliliter (mg/ml)], and a "firstnucleation product" is precipitated by rapid titration andcentrifugation. The remaining supernatant (containing the bulk of theoriginal collagen) is then decanted and allowed to stand overnight. Theprecipitated second nucleation product is collected by centrifugation.

Copending U.S. patent application Ser. No. 07/433,441; pendingincorporated herein by reference, discloses an improved injectablecollagen formulation which is conjugated to a chemically activatedpolymer, such as polyethylene glycol. The conjugated collagen hasimproved persistence at the implantation site. Also disclosed in thepending application is a method for crosslinking the collagen materialwith a bifunctional-activated polymer in situ, such as polyethyleneglycol. This improved process method allows the collagen implant to becrosslinked to the host tissue by the activated polymer.

Another embodiment of the biomaterial to be used in the inventionincludes a high collagen concentration formulation, which is disclosedin U.S. patent application Ser. No. 07/843,770, filed Feb. 28, 1992;abandoned incorporated herein by reference. Briefly, collagen insolution (Vitrogen 100 Collagen, Celtrix Laboratories, Palo Alto,Calif.) is reconstituted to fibril form by neutralizing the solutionwith the addition of a phosphate buffer at ambient temperatures. Theresultant fibrillar collagen may be optionally crosslinked usingstandard techniques known in the art prior to concentration. The highconcentration collagen materials disclosed herein are passed through ahomogenizer (HC5000, Microfluidics Corporation, Newton, Mass.) toimprove the extrudability of the material through a fine gauge needle.High concentrations of non-crosslinked and crosslinked fibrillarcollagen are expected to have improved persistence compared tocommercially available forms.

Another particularly useful biomaterial to be used in the disclosedinvention is described in U.S. patent application Ser. No. 07/843,646,filed Feb. 28, 1992; abandoned (Attorney Number 05921-11) incorporatedherein by reference, which describes an injectable collagen/ceramicformulation. Briefly, porous and/or non-porous ceramic particles areprepared to have a uniform particle size distribution in the range ofabout 50-250 microns. The preferred ceramic particles are admixed withfibrillar collagen to produce an injectable ceramic/collagenformulation. The addition of the ceramic particles improves thepersistence of the injectable collagen formulation.

Other commercially available biomaterials useful in the describedinvention are a polytetrafluoride (Teflon) paste, known as PolytefPaste, and a porcine collagen particulate suspended in saline, known asFibrel Gelatin Matrix Implant (both available from Mentor Corporation,Santa Barbara, Calif.). Further biomaterials include fluid suspensionscontaining: gelatin beads, glass beads, hydrogel beads, silicone rubberor carbide beads, polytetrafluoride beads, and the like.

An effective amount of wound healing agents may be added to thebiomaterial used in the invention to improve long-term restoration ofthe sphincter defect. These agents include protein growth factors suchas fibroblast growth factors (FGFs), platelet derived growth factors(PDGFs), epidermal growth factors (EGFs), connective tissue activatedpeptides (CTAPs), transforming growth factors (TGFs), and the like.These biologically active agents are known to facilitate regrowth ofconnective tissue cells and accumulation of fibroblasts, endothelialcells, and wound healing regulatory cells to speed wound healing. One ormore of these agents in combination can be used in the invention. Theamount of wound healing agent(s) to be included with the biomaterial mayvary, depending upon the biomaterial used, the patient (age, sex,medical history) and the site being treated. Typically the weight ratioof wound healing agent(s) to the biomaterial would be in the range ofabout 1:5,000 to 1:50,000.

The wound healing agents may be isolated from native or natural sources,such as from mammalian cells, or may be prepared synthetically, such asby recombinant DNA or by chemical processes. In addition, analogs,fragments, or derivatives of these agents may be used, provided theyexhibit some of the biological activity or wound healing properties ofthe native molecule. For example, analogs can be prepared by expressionof genes altered by site-specific mutagenesis or other geneticengineering techniques.

These agents may be added to the biomaterial during preparation or justprior to treatment. It is preferred that the wound healing agents beincorporated into the biomaterial such that the agents are releasedthrough a sustained delivery. In this way, the agents can be releasedover an extended period of time into the anal sphincter sites andsurrounding areas, promoting wound healing. It is most preferred thatthese agents will be included in the patient's treatment in thoseinstances where the biomaterial is being used to repair the analsphincter muscles.

Optionally, antimicrobial additives and/or antibodies may be added tothese biomaterials to reduce the potential for infection at thetreatment site. In addition, local anesthetics may be used at theinjection site. Any appropriate additive may be utilized as long as itis compatible with the biomaterial used and the patient.

A preferred method of the invention is performed in an outpatientsetting under aseptic conditions with the patient in the lithotomyposition. A retractor is used to clearly visualize the anal orifice andthe biomaterial is typically supplied in a sterile 3.0 cubic centimeters(cc) syringe fitted with a 25 gauge needle.

An anorectal examination is preferably conducted prior to treatment. Theexamination includes direct visualization of the lower rectum and analcanal, as well as palpation of the perianal area and anorectal ring. Ananoscope (a metal device approximately three inches in length) will beused to visualize the tissues of the anal canal and lower rectum; thesphincter mass and function will be assessed by palpation of thesphincter mechanism while the patient is asked to strain and squeeze.Pre-examination preparation is not required (i.e., Fleet enema) and theexamination is of minimal duration (1-2 minutes).

When repairing structurally defective sphincters, such as a keyholedeformity resulting from surgery or trauma, the biomaterial, optimallycontaining wound healing agents, is injected perianally into thedeformity, using one or more injections, until the physician observesthat the treated area has been restored to its original form and thedefect is repaired (i.e., the hole or defect is no longer visible to theskilled physician). The patient's continence level is then measuredusing standard manometry.

The process of evaluating anal continence is divided into two areas:subjective reporting of the patient's symptoms and objective measurementof the change in anal sphincter pressure.

A scale has been created to measure change in patients' reporting oftheir symptoms. The data being measured includes complaints of itching,bleeding, difficulty or ease of evacuation, nocturnal sleep disturbance,staining of undergarments, prolapse of tissue, and need for other formsof therapy. Typically the scale is as follows (based upon degree ofcomplaint): 1+=minimal complaint, 2+=moderate, 3+=severe, and4+=incapacitating.

Objective data is obtained through the use of anal manometry. Manometry,by measurement of pressure, supplies information about muscle activityat the time of actual measurement. Baseline continence levels aremeasured both prior to and following treatment. Anal manometricevaluation helps to define the results of improved continence based uponthe pressures obtained pre- and post-treatment. The apparatus usedtypically comprises a four-channel radially perfused balloon-tippedcatheter, pressure transducers, and a multichannel recorder. Thefollowing are measured and are recorded on the appropriate medicalrecord: resting squeeze pressure, maximal squeeze pressure, anorectalreflex, and threshold volume. Although anal manometry will showvariations during the course of the day, measuring basal and openingpressures before and after injection in the same patient will allow fordetermination of the efficacy of the technique on increasing analsphincter pressure. Each patient will therefore act as his/her owncontrol.

To improve, restore, and/or supplement the competency of the incompetentsphincters, the biomaterial is injected into the submucosa of the analsinuses. It is important that the biomaterial is not injected into theblood vessels, as this may cause vascular occlusion, infarction, orembolic phenomena. A preferred amount of biomaterial to be used in therepair of structural defects varies from patient to patient, however, isabout between 1-40 cc.

A preferred amount of biomaterial to be used is about between 15-40 cc,most preferably about 20-30 cc for augmentation of the anal sphincters;whereas about 5-10 cc of biomaterial may be used in muscle repair. Theamount of material necessary to effect repair of structural defects orrestoration of competency will, of course, vary with the degree oftissue loss or destruction to the area. Alternatively, the treatingphysician may wish to augment treatment for repairing structurallydefective sphincters by injecting the biomaterial, optionally containingwound healing agent(s), into the submucosa of the anal sinuses, beforeor after perianal injection of the biomaterial into the defect orstructural deformity. Then the patient's continence level is measuredusing standard manometry. Successful treatment is also defined in termsof the patient's report of a decrease in incontinent episodes.

Improvements in continence and repair of damaged tissue is expected tolast a minimum of about 3 to 6 months. The injections may optionally berepeated on a regular basis to maintain continence and correction ofdamaged tissue. It is expected that subsequent injections will requireless material than the initial treatment.

Methods for repairing structurally defective or inadequately functioningmuscles of the anal sphincters may be conducted by perianallyadministering an injectable biomaterial, with or without wound healingagents, into the structural deformity. Also disclosed are methods forimproving the competency of the anal sphincter by administering aninjectable biomaterial into the anal sinuses. These methods providenonsurgical approaches for treating anorectal incontinence.

The following experimental section is offered by way of example and notby limitation. The invention is described below in some detail for thepurposes of clarity and understanding. It will be apparent, however,that certain changes and modifications may be practiced within the scopeof the appended claims.

EXPERIMENTAL

A patient presented a complaint of anal leakage secondary to a posterioranal (keyhole) deformity which was secondary to excision of a fissureseveral years before. Local care failed to control the symptoms of analleakage and, approximately three months later, a sphincteroplasty andloop sigmoid colostomy were performed. About two months later closure ofthe colostomy was accomplished and the patient remained continent forabout six months. Due to the marked scarring in the area of the analsphincter surgery, the repair slowly failed and within ten months of thecolostomy closure, the patient again had marked anal leakage.

Because of the patient's refusal to undergo further surgery, a decisionwas made to "bolster" the defect and enhance the sphincter function withan injection of commercially available atelopeptide fibrillar collagen.Twenty cc of collagen was injected into the defect and surroundingtissues without any analgesia or anesthesia in an outpatient setting.For six months the patient remained completely continent without anysymptoms. At that point, signs and symptoms of anal leakage developed.

What is claimed is:
 1. A method of improving the competency of incompetent anal sphincters comprising (1) selecting an injectable biomaterial capable of persisting at a site of its injection for at least three months, and (2) injecting an effective amount of the injectable material into the anal sinuses between the blood vessels, sufficient to improve competency of the incompetent anal sphincter.
 2. The method of claim 1, wherein said injectable biomaterial comprises atelopeptide fibrillar, crosslinked or non-crosslinked collagen.
 3. The method of claim 1, wherein said injectable biomaterial is an aqueous suspension of a material selected from the group consisting of atelopeptide fibrillar, crosslinked collagen, non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogen beads, silicon carbide beads and glass beads, with a biocompatible fluid lubricant.
 4. The method of claim 3 wherein said biocompatible fluid lubricant is selected from the group consisting of: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, and heparin.
 5. The method of claim 1, wherein said injectable biomaterial is a second nucleation collagen.
 6. The method of claim 2 wherein said collagen is conjugated to a chemically activated polymer.
 7. The method of claim 6 wherein said chemically activated polymer is polyethylene glycol.
 8. The method of claim 2 wherein said collagen is crosslinked with a bifunctional activated polymer.
 9. The method of claim 8 wherein said collagen and said bifunctional activated polymer crosslink in situ.
 10. The method of claim 8 wherein said bifunctional activated polymer is polyethylene glycol.
 11. The method of claim 2 wherein said biomaterial further comprises a ceramic and/or mineral material.
 12. The method of claim 11 wherein said ceramic material comprises ceramic particles in the size range of about 50-250 microns.
 13. The method of claim 1 wherein said biomaterial further comprises an antimicrobial additive and/or antibiotic. 